This research will develop, characterize and optimize a novel synthetic gene delivery system for the delivery of the human cystic fibrosis transmembrane conductance regulator encoding DNA to human airway epithelial and submucosal cells in the lung. The delivery system consists of a targeting ligand, membrane destabilizing component, nuclear entry component, DNA condensor and DNA masking component that form a complex directly with the DNA. The targeting ligand is attached to the DNA via a DNA intercalator or via electrostatic interactions. The membrane destabilizing component is a membrane active peptide that facilitates transmembrane transfer of DNA. The current version of the complex is between 20 to 100 times more effective than the cationic lipid DOTMA at mediating transfection of cells in culture. The research plan has four interacting components: 1. Synthesis of the delivery ligands and membrane destabilizers 2. Optimization and characterization of the transfection system in cultured cells and rat lung using reporter genes, 3. Transfection of CFTR into cultured human primary airway and serous cells and assessment of function. 4. Transfection of CFTR into rat and ferret lung via the airway or the parenteral route and characterization of the extent, duration and location of expression of human CFTR.